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UK paracetamol overdose rate ‘twice the European average’

Acute liver failure caused by paracetamol overdosing is twice as common in the UK as in other European countries, a study of data from the mid-2000s has revealed.

The study – published in the British Journal of Clinical Pharmacology – found that overall, paracetamol overdoses accounted for a sixth of all cases of acute liver failure resulting in transplant (ALFT) in European countries between 2005 and 2007.

However, rates of paracetamol overdose related ALFT varied massively between countries and were highest in Ireland and the UK.

For example, Ireland had 49 cases and the UK 10 cases per 1,000 tons of paracetamol sold – compared with an average of six.

Just three paracetamol related ALFT cases occurred in France, four in the Netherlands and one in Italy – while Greece and Portugal recorded no overdose-related ALFTs.  

By contrast there was little variation in non-overdose related cases of ALFTs. The study authors said this suggested there is an overall higher rate of paracetamol overdose in the UK and Ireland than elsewhere, rather than more cases of severe overdose.

Lead researcher Professor Sinem Ezgi Gulmez, associate professor of pharmacology at the University of Bordeaux, France, said:  ‘Overall, we found a six-times higher risk in Ireland and a two-fold higher risk in the UK compared to the average of the countries participating in the study.’

Professor Gulmez added: ‘Since we do not have event rates for overdoses not leading to liver failure, we cannot conclude anything about the rates of non-ALFT overdoses in the different countries, but indicators point to more common use of paracetamol for self-poisoning in these countries.’

Br J Clin Pharm 2015; available online 28 May

Readers' comments (5)

  • Vinci Ho

    A different angle of looking at this matter:
    (1) What is the prevalence of chronic pain in UK as compared to other countries? Associated factors like obesity may have to be considered.
    (2) What are other options for relieving pain available in UK (hence,NHS)apart from using pills? What is the comparable availability in other countries?
    (3) Ireland's figure seems to be even more disproportionate :49/1000, any apparent explanation?

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  • Vinci Ho

    Somehow people in UK and Ireland prefer a 'culture' of using paracetamol as a mean in self harm and acute liver failure as a result of paracetamol overdose is more likely to occur in these countries , genetically determined??
    Packet size apparently matters as well
    The discussion of the article offers some insight :

    Discussion
    In the present study, which compiled exhaustively all cases of liver transplantation over 3 years in seven countries [1, 2], paracetamol was involved in 111/114 (97.3%) ALFTs. The three other cases involved opiates (possibly hepatotoxic due to biliary spasm), ecstasy (where the use of other drugs of abuse cannot be eliminated), and diclofenac + iron (where the role of acute iron overdose may be suspected). Like most NSAIDs, diclofenac is associated with liver toxicity, but this is idiosyncratic and usually not related to overdose [1]. We cannot eliminate that these three cases might also have ingested paracetamol without it being recorded.

    The method we used within the liver transplant units, coupled with the transplant registries, ensured that we missed no cases of ALFT, whatever the cause, over the period and area of the study. Because paracetamol overdose is one of the main causes of ALF, it is highly unlikely that paracetamol overdose would not have been sought as an explanation in a case of otherwise unexplained ALF, from patient history or family, or biological indicators of paracetamol poisoning. The course of ALF caused by paracetamol overdose is well known, and usually progressive over a few days, so that the hypothesis of acute overdoses leading to fatal liver failure that would not reach the hospital is unlikely unless the patient specifically refused admission. Overdose represented 10–50% of ALFT according to the country.

    The total amount of paracetamol sold per country can be ascertained from wholesalers and manufacturers. IMS has a strong reputation for providing reliable sales figures; these include pharmacy and non-pharmacy sales but do not cover ‘grey market’ sales – i.e. parallel imports, sales over the internet or products bought abroad, or the export of the drug to other countries [10-12]. Other studies have not used exhaustive nationwide data from transplantation registries and therefore have not provided the information per million inhabitants or per ton of paracetamol sold nationwide [13].

    The event rate for paracetamol overdose-related ALFT was not found to be homogeneous throughout Europe. It ranged from no cases in Greece or Portugal, out of about 10 million persons each, over 3 years, to one case in 60 million inhabitants over 3 years in Italy, to one per 0.3 million per year in Ireland – a 200-fold difference. The event rate per ton of paracetamol sold was also very variable, ranging from one overdose ALFT for 1074 tons of paracetamol sold in Italy, to one for 20.7 tons sold in Ireland. Per-person use of paracetamol ranged from 3.5 tons per million inhabitants per year in Portugal, to 51.5 tons in France. The highest rates of overdose ALFT per ton of paracetamol sold or per inhabitant were found in the two English-speaking countries (Ireland and the UK).

    There are two hypotheses to explain the latter result: that there is a higher overall rate of paracetamol overdose in these two countries, with the same proportion of the more severe ones leading to transplantation; or that, for some reason, overdoses may be more severe in these countries, resulting in more severe liver failure, suggesting a possible genetic or a societal background for this higher incidence of ALFT. However, the fact that non-overdose ALFT occurs with about the same incidence in all European countries is an argument against a genetic predisposition to more severe hepatic injuries, and probably also against an environmental or societal explanation such as per capita alcohol consumption, which is highest in Portugal and France according to the World Health Organization [14]. As we do not have event rates for overdoses not leading to liver failure, we cannot conclude on rates of non-ALFT overdoses in the different countries, but indicators point to more common use of paracetamol for self-poisoning in these countries.

    There was no relationship between the amount of paracetamol used yearly per million inhabitants and the number of overdoses per inhabitant or per ton of paracetamol sold. Reducing total or per capita use of paracetamol in a country would not necessarily reduce the number of acute drug overdoses leading to transplantation. France has the highest per capita use of paracetamol but the third lowest ALFT rate.

    Changing the amount per preparation or per box might change the risk of liver failure. In Ireland, legislation was introduced in October 2001 to control the sale of paracetamol in non-pharmacy outlets. Donohoe et al. assessed the impact of this legislation on acute deliberate paracetamol overdoses and concluded that the legislation controlling the sales and packaging of paracetamol preparations appeared to be associated with a significant fall in the number of tablets taken in acute deliberate paracetamol overdoses [15]. Despite this, paracetamol overdose was still involved in over 50% of all ALFTs in Ireland [16]. In the UK, paracetamol was found to be the principal cause of poison-related deaths and liver transplants for ALF [17]. Paracetamol overdose accounted for about 40% of cases of ALF in the UK [18], and also accounted for over 200 admissions to a liver unit and 20 or so liver transplants per year [19]; our results were similar (i.e. 60 overdose ALFTs over 3 years in SALT in the UK), which confirms the validity of both studies. In a recent study by Teo et al., in adults (>13 years) admitted to the emergency department short-stay ward of Aberdeen Royal Infirmary in 2009 because of poisoning, almost half of 1062 cases were polypharmacy; alcohol was involved in 40% of cases and overdoses most commonly involved paracetamol (43%) [20]. As paracetamol hepatotoxicity is the leading cause of overdose ALFT and yet is completely preventable, regulatory changes regarding the labelling and dispensing of paracetamol-containing products have been implemented [21-23]. In the UK, blister packaging and restrictions on the dispensing of paracetamol tablets in 1998 led to a reduction in the number of patients intentionally overdosing and of those referred for liver transplantation during the 11 years after the introduction of the legislation [24-26]. Despite this, after Ireland, the UK remains the country with the highest rate of ALFT due to paracetamol overdose per million inhabitants or per ton of paracetamol sold. The number of cases we found in SALT was too small to derive temporal trends over only 3 years. Paracetamol overdose was responsible for only 1.0% of all-cause ALFT in Italy, and no cases of overdose ALFT were identified in Greece or Portugal. In a recent retrospective study [27] analysing the results of liver transplantation for ALF in the region of Castilla y Leon in Spain, the most common aetiology was toxic exposure to agricultural products. No cases were related to paracetamol overdose, which is reported to be a rare cause of ALF in Spain [28].

    The present study was the first population-based study of paracetamol overdose leading to registration for liver transplantation. Most studies of drug-induced liver injury often have as the point of capture admittance to emergency or hepatology departments, and have only provided the relative weight of ALF sent for transplantation out of all cases of ALF or all acute overdoses, rather than absolute numbers. As in the present study, they found paracetamol overdose to be the leading cause of ALFT, representing up to 50% of all such cases. Overdose ALFT represents only a small percentage of all liver transplants (1%) but a non-negligible proportion (1/6) of cases of unexplained or drug-related ALF [1, 2]. This avoidable cause deprives other potential recipients of a much-needed organ. There is a need to continue working on avoiding overdose ALFT. Reducing pack size is a likely answer, and seems to have worked in the UK. In France, pack sizes were limited to 8 g per pack some time ago.

    It is unlikely that limiting individual tablet strength for prescription paracetamol in the US would be efficient at preventing overdose ALFT when paracetamol can still be bought over the counter at doses of 500 mg or 1 g per tablet in large pack sizes. These large pack sizes make large amounts of a dangerous product easily available for an impulse overdose. This is not the case for limited pack sizes in blister packs, as found in other countries for over-the-counter usage. However, this is certainly not the only reason for the differences in event rates between countries, and more work needs to be done to understand why people in Ireland and the UK commit suicide more often with paracetamol than in other countries, or at least have more cases of ALFT.


    Conclusion
    Paracetamol is still the almost exclusive cause for liver transplantation related to acute drug overdose, with an average of one case per 6 million inhabitants per year over seven countries in Europe. This seems to be about eight times less than the number reported for the US.
    Large differences were found between countries in event rates, with a six-times higher risk in Ireland and a two-fold higher risk in the UK compared with the average of the countries participating in the study. The reasons for these differences are uncertain but could give indications for their prevention.

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  • John Glasspool

    The last time I was in the USA, OTC paracetamol was quite expensive IIRC. However, if we do that here then everyone will be at the GPs for paracetamol scripts. Good if we get round to paying GPs per consultation!

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  • Start selling pure Codeine rather than insisting it is compounded with Paracetamol or Ibuprofen and watch these rates drop.

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  • ....or restore co-codamol back to POM. And anything compounded with codeine\dhydrocodeine that matter!

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